Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death.

Abstract:

:Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated sodium channel NaV1.1. Brain NaV1.1 is primarily localized to fast-spiking inhibitory interneurons; thus the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of NaV1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy.

authors

Richards KL,Milligan CJ,Richardson RJ,Jancovski N,Grunnet M,Jacobson LH,Undheim EAB,Mobli M,Chow CY,Herzig V,Csoti A,Panyi G,Reid CA,King GF,Petrou S

doi

10.1073/pnas.1804764115

subject

Has Abstract

pub_date

2018-08-21 00:00:00

pages

E8077-E8085

issue

34

eissn

0027-8424

issn

1091-6490

pii

1804764115

journal_volume

115

pub_type

杂志文章
  • 1H-Observe/13C-decouple spectroscopic measurements of lactate and glutamate in the rat brain in vivo.

    abstract::We have used (13C)-1H NMR spectroscopy at 360.13 MHz to resolve the 13C coupled proton resonance of glutamate and lactate in the rat brain in vivo. The time required for the 13C fractional enrichment of the 4-CH2 position of brain glutamate to reach isotopic steady state was determined during a continuous infusion of ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.82.6.1633

    authors: Rothman DL,Behar KL,Hetherington HP,den Hollander JA,Bendall MR,Petroff OA,Shulman RG

    更新日期:1985-03-01 00:00:00

  • Gene flow from North Africa contributes to differential human genetic diversity in southern Europe.

    abstract::Human genetic diversity in southern Europe is higher than in other regions of the continent. This difference has been attributed to postglacial expansions, the demic diffusion of agriculture from the Near East, and gene flow from Africa. Using SNP data from 2,099 individuals in 43 populations, we show that estimates o...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 历史文章,杂志文章

    doi:10.1073/pnas.1306223110

    authors: Botigué LR,Henn BM,Gravel S,Maples BK,Gignoux CR,Corona E,Atzmon G,Burns E,Ostrer H,Flores C,Bertranpetit J,Comas D,Bustamante CD

    更新日期:2013-07-16 00:00:00

  • Interkingdom metabolic transformations captured by microbial imaging mass spectrometry.

    abstract::In polymicrobial infections, microbes can interact with both the host immune system and one another through direct contact or the secretion of metabolites, affecting disease progression and treatment options. The thick mucus in the lungs of patients with cystic fibrosis is highly susceptible to polymicrobial infection...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1206855109

    authors: Moree WJ,Phelan VV,Wu CH,Bandeira N,Cornett DS,Duggan BM,Dorrestein PC

    更新日期:2012-08-21 00:00:00

  • Reconstructing the pathways of a cellular system from genome-scale signals by using matrix and tensor computations.

    abstract::We describe the use of the matrix eigenvalue decomposition (EVD) and pseudoinverse projection and a tensor higher-order EVD (HOEVD) in reconstructing the pathways that compose a cellular system from genome-scale nondirectional networks of correlations among the genes of the system. The EVD formulates a genes x genes n...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0509033102

    authors: Alter O,Golub GH

    更新日期:2005-12-06 00:00:00

  • Mechanisms and plasticity of chemogenically induced interneuronal suppression of principal cells.

    abstract::How do firing patterns in a cortical circuit change when inhibitory neurons are excited? We virally expressed an excitatory designer receptor exclusively activated by a designer drug (Gq-DREADD) in all inhibitory interneuron types of the CA1 region of the hippocampus in the rat. While clozapine N-oxide (CNO) activatio...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2014157118

    authors: Rogers S,Rozman PA,Valero M,Doyle WK,Buzsáki G

    更新日期:2021-01-12 00:00:00

  • A Fas-associated protein factor, FAF1, potentiates Fas-mediated apoptosis.

    abstract::Fas, a member of the tumor necrosis factor receptor family, can induce apoptosis when activated by Fas ligand binding or anti-Fas antibody crosslinking. Genetic studies have shown that a defect in Fas-mediated apoptosis resulted in abnormal development and function of the immune system in mice. A point mutation in the...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.25.11894

    authors: Chu K,Niu X,Williams LT

    更新日期:1995-12-05 00:00:00

  • Effects of glycyl-L-glutamine and methylprednisolone on maintenance of acetylcholinesterase of transected rat sciatic nerves.

    abstract::Under anesthesia with sodium pentobarbital, the sciatic nerves of rats were transected bilaterally, and a catheter was inserted into the central end of the left renal artery. After an initial flush, an Alzet pump was attached to the catheter, containing various concentrations of glycyl-L-glutamine (Gly-Gln), methylpre...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.23.9495

    authors: Koelle GB,Han MS

    更新日期:1990-12-01 00:00:00

  • The crystal structure of Pyrococcus furiosus ornithine carbamoyltransferase reveals a key role for oligomerization in enzyme stability at extremely high temperatures.

    abstract::The Pyrococcus furiosus (PF) ornithine carbamoyltransferase (OTCase; EC 2.1.3.3) is an extremely heat-stable enzyme that maintains about 50% of its activity after heat treatment for 60 min at 100 degrees C. To understand the molecular basis of thermostability of this enzyme, we have determined its three-dimensional st...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.6.2801

    authors: Villeret V,Clantin B,Tricot C,Legrain C,Roovers M,Stalon V,Glansdorff N,Van Beeumen J

    更新日期:1998-03-17 00:00:00

  • Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism.

    abstract::Three-prime repair exonuclease 1 knockout (Trex1-/-) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-def...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1611113114

    authors: Hasan M,Gonugunta VK,Dobbs N,Ali A,Palchik G,Calvaruso MA,DeBerardinis RJ,Yan N

    更新日期:2017-01-24 00:00:00

  • Inhibition of growth of pancreatic carcinomas in animal models by analogs of hypothalamic hormones.

    abstract::Using animal models of acinar and ductal pancreatic cancer, we investigated the effect of analogs of hypothalamic hormones on tumor growth. In Wistar/Lewis rats bearing the acinar pancreatic tumor DNCP-322, chronic administration of [L-5-Br-Trp8]somatostatin-14 significantly decreased tumor weights and volume. Somatos...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.1.248

    authors: Redding TW,Schally AV

    更新日期:1984-01-01 00:00:00

  • Mycobacterium bovis Bacille Calmette-Guérin strains secreting listeriolysin of Listeria monocytogenes.

    abstract::Recombinant (r) Mycobacterium bovis strains were constructed that secrete biologically active listeriolysin (Hly) fusion protein of Listeria monocytogenes. The r-BCG strains pAT261:Hly or pMV306:Hly expressed plasmid multicopies or chromosomal single copies of the hly gene, respectively. Human and murine macrophage-li...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.9.5299

    authors: Hess J,Miko D,Catic A,Lehmensiek V,Russell DG,Kaufmann SH

    更新日期:1998-04-28 00:00:00

  • Microsatellite instability in Drosophila spellchecker1 (MutS homolog) mutants.

    abstract::We have cloned a mutS homolog from Drosophila melanogaster called spellchecker1 (spel1) and have constructed spel1 mutant flies. MutS proteins promote the correction of DNA mismatches and serve important roles in DNA replication, recombination, and repair. The spel1 gene belongs to a subfamily of mutS first characteri...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.6.2964

    authors: Flores C,Engels W

    更新日期:1999-03-16 00:00:00

  • Secretory proteins induced in human fibroblasts under conditions used for the production of interferon beta.

    abstract::Human fibroblast cells treated with a combination of inhibitors of protein and RNA synthesis [cycloheximide and actinomycin D as used to superinduce interferon beta (IFN-beta)] secrete two proteins with molecular masses of 22000 and 27000 kilodaltons (called 22-kDal and 27-kDal) that are precipitable with an antiserum...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.9.2768

    authors: Content J,De Wit L,Pierard D,Derynck R,De Clercq E,Fiers W

    更新日期:1982-05-01 00:00:00

  • Use of engineered ribozymes to catalyze chimeric gene assembly.

    abstract::We report the use of engineered ribozymes to shuffle exon cassettes in vitro. Specifically, we have designed derivatives of a group II intron that insert into selected sites in the human tissue plasminogen activator (t-PA) mRNA. The insertion reaction links t-PA sequences to the group II intron sequences so that trans...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.15.7486

    authors: Mikheeva S,Jarrell KA

    更新日期:1996-07-23 00:00:00

  • Energy transfer between photosystem II units in a connected package model of the photochemical apparatus of photosynthesis.

    abstract::A model of the photochemical apparatus of photosynthesis, presented previously in a tripartite format, is used in a bipartite format to analyze energy transfer between photosystem II units. The model is used to develop analytical expressions for the photochemical properties of chloroplasts that include a term for the ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.8.4697

    authors: Butler WL

    更新日期:1980-08-01 00:00:00

  • Dorsal periaqueductal gray-amygdala pathway conveys both innate and learned fear responses in rats.

    abstract::The periaqueductal gray (PAG) and amygdala are known to be important for defensive responses, and many contemporary fear-conditioning models present the PAG as downstream of the amygdala, directing the appropriate behavior (i.e., freezing or fleeing). However, empirical studies of this circuitry are inconsistent and w...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1310845110

    authors: Kim EJ,Horovitz O,Pellman BA,Tan LM,Li Q,Richter-Levin G,Kim JJ

    更新日期:2013-09-03 00:00:00

  • Torque measurements reveal sequence-specific cooperative transitions in supercoiled DNA.

    abstract::B-DNA becomes unstable under superhelical stress and is able to adopt a wide range of alternative conformations including strand-separated DNA and Z-DNA. Localized sequence-dependent structural transitions are important for the regulation of biological processes such as DNA replication and transcription. To directly p...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1113532109

    authors: Oberstrass FC,Fernandes LE,Bryant Z

    更新日期:2012-04-17 00:00:00

  • The axonal attractant Netrin-1 is an angiogenic factor.

    abstract::Blood vessels and nerves often follow parallel trajectories, suggesting that distal targets use common cues that induce vascularization and innervation. Netrins are secreted by the floor plate and attract commissural axons toward the midline of the neural tube. Here, we show that Netrin-1 is also a potent vascular mit...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0405984101

    authors: Park KW,Crouse D,Lee M,Karnik SK,Sorensen LK,Murphy KJ,Kuo CJ,Li DY

    更新日期:2004-11-16 00:00:00

  • Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy.

    abstract::Genetic analysis of Parkinson disease (PD) has identified several genes whose mutation causes inherited parkinsonism, as well as risk loci for sporadic PD. PTEN-induced kinase 1 (PINK1) and parkin, linked to autosomal recessive PD, act in a common genetic pathway regulating the autophagic degradation of mitochondria, ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1321207111

    authors: Ivatt RM,Sanchez-Martinez A,Godena VK,Brown S,Ziviani E,Whitworth AJ

    更新日期:2014-06-10 00:00:00

  • Shear stress activates mitochondrial oxidative phosphorylation by reducing plasma membrane cholesterol in vascular endothelial cells.

    abstract::Vascular endothelial cells (ECs) sense and respond to hemodynamic shear stress, which is critical for circulatory homeostasis and the pathophysiology of vascular diseases. The mechanisms of shear stress mechanotransduction, however, remain elusive. We previously demonstrated a direct role of mitochondria in the purine...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2014029117

    authors: Yamamoto K,Nogimori Y,Imamura H,Ando J

    更新日期:2020-12-29 00:00:00

  • Compounds I of catalase and horse radish peroxidase: pi-cation radicals.

    abstract::Two-electron oxidation of cobaltous octaethylporphyrin [Co(II)(Et)(8)P] yields a stable pi-cation radical [Co(III)(Et)(8)P](2+.), the optical spectrum of which exhibits spectral changes dependent upon the nature of the counterion. Comparison of these spectra with those of Compounds I of horseradish peroxidase and cata...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.68.3.614

    authors: Dolphin D,Forman A,Borg DC,Fajer J,Felton RH

    更新日期:1971-03-01 00:00:00

  • The insect neuropeptide prothoracicotropic hormone is released with a daily rhythm: re-evaluation of its role in development.

    abstract::Prothoracicotropic hormone (PTTH) is the central cerebral neurohormone in insect development. Its release has been believed for decades to be confined to one (or two) critical moments early in each developmental stage at which time it triggers prolonged activation of the prothoracic glands to synthesize and release th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.8.3368

    authors: Vafopoulou X,Steel CG

    更新日期:1996-04-16 00:00:00

  • ELL2, a new member of an ELL family of RNA polymerase II elongation factors.

    abstract::We recently isolated an RNA polymerase II elongation factor from rat liver nuclei and found it to be homologous to the product of the human ELL gene, a frequent target for translocations in acute myeloid leukemia. To further our understanding of the possible role(s) of ELL in transcriptional regulation and human disea...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.8.3639

    authors: Shilatifard A,Duan DR,Haque D,Florence C,Schubach WH,Conaway JW,Conaway RC

    更新日期:1997-04-15 00:00:00

  • Thermotaxis by pseudoplasmodia of Dictyostelium discoideum.

    abstract::The temperature dependence of migration rate and of the thermotactic sensitivity of pseudoplasmodia of Dictyostelium discoideum has been measured. Migration rate increases with temperature to 20 degrees, is temperature insensitive from 20 degrees to 27.5 degrees, and decreases with temperature to 29 degrees, above whi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.74.5.2007

    authors: Poff KL,Skokut M

    更新日期:1977-05-01 00:00:00

  • A response regulator of cyanobacteria integrates diverse environmental signals and is critical for survival under extreme conditions.

    abstract::Microorganisms must sense their environment and rapidly tune their metabolism to ambient conditions to efficiently use available resources. We have identified a gene encoding a response regulator, NblR, that complements a cyanobacterial mutant unable to degrade its light-harvesting complex (phycobilisome), in response...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.18.11008

    authors: Schwarz R,Grossman AR

    更新日期:1998-09-01 00:00:00

  • An accumulator model for spontaneous neural activity prior to self-initiated movement.

    abstract::A gradual buildup of neuronal activity known as the "readiness potential" reliably precedes voluntary self-initiated movements, in the average time locked to movement onset. This buildup is presumed to reflect the final stages of planning and preparation for movement. Here we present a different interpretation of the ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1210467109

    authors: Schurger A,Sitt JD,Dehaene S

    更新日期:2012-10-16 00:00:00

  • Molecular, functional, and evolutionary analysis of sequences specific to Salmonella.

    abstract::In that salmonellae have been implicated in an unprecedented array of diseases, sequences found to be specific to this species are often thought to be involved in the virulence attributes not seen in other enteric bacteria. To identify the molecular, genetic, and phenotypic characteristics that differentiate bacterial...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.3.1033

    authors: Groisman EA,Sturmoski MA,Solomon FR,Lin R,Ochman H

    更新日期:1993-02-01 00:00:00

  • Induction of cyclin D1 by simian virus 40 small tumor antigen.

    abstract::Cell-cycle progression is mediated by a co-ordinated interaction between cyclin-dependent kinases and their target proteins including the pRB and E2F/DP-1 complexes. Immunoneutralization and antisense experiments have established that the abundance of cyclin D1, a regulatory subunit of the cyclin-dependent kinases, ma...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.23.12861

    authors: Watanabe G,Howe A,Lee RJ,Albanese C,Shu IW,Karnezis AN,Zon L,Kyriakis J,Rundell K,Pestell RG

    更新日期:1996-11-12 00:00:00

  • Synthesis of collagen by chondrocytes in suspension culture: modulation by calcium, 3':5'-cyclic AMP, and prostaglandins.

    abstract::Rabbit articular chondrocytes synthesize type II collagen [3alpha(1)(II)] in vivo and type I collagen [2alpha(1)(I).alpha(2)] in monolayer cultures. In suspension culture the nature of phenotype depends on extracellular Ca(2+). The relationship of Ca(2+) and 3':5'-cyclic AMP (cAMP) in regulation of collagen synthesis ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.74.9.3864

    authors: Deshmukh K,Sawyer BD

    更新日期:1977-09-01 00:00:00

  • Methyl-directed repair of frameshift mutations in heteroduplex DNA.

    abstract::DNA heteroduplexes with single unpaired bases of the four different kinds were prepared by annealing separated strands of bacteriophage lambda DNA and used to transfect Escherichia coli. Genetic analysis of the progeny phages obtained from transfected bacteria indicates that the E. coli mismatch repair system can reco...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.10.3395

    authors: Dohet C,Wagner R,Radman M

    更新日期:1986-05-01 00:00:00